title: Secreted amyloid precursor protein alpha selectively suppresses N-methyl-D-aspartate currents in hippocampal neurons: involvement of cyclic GMP.
abstract: The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner; data suggest sAPP alpha may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPP alpha can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. We now report whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons which demonstrate that sAPP alpha selectively suppresses N-methyl-D-aspartate currents without affecting currents induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPP alpha suppressed N-methyl-D-aspartate current rapidly and reversibly at concentrations of 0.011 nM. Suppression of N-methyl-D-aspartate current by sAPP alpha is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-D-aspartate current in a manner similar to sAPP alpha, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevented sAPP alpha-induced suppression of N-methyl-D-aspartate current. In addition, okadaic acid prevented suppression of N-methyl-D-aspartate-induced current suggesting the involvement of a protein phosphatase in modulation of N-methyl-D-aspartate current by sAPP alpha. These data identify a mechanism whereby sAPP alpha can modulate cellular responses to glutamate, and suggest important roles for sAPP alpha in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate.
authors.affiliation: Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D006152:Cyclic GMP; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate